The human genome is organized in a highly ordered DNA-histone complex that is subject to a variety of developmentally regulated covalent modifications to constitute a specific epigenome. The post-translational modifications of histones play critical roles in regulating genome-wide gene expression program. We have generated the first comprehensive epigenomic map of human T cells for the major histone modifications including diacetylation of histone H3 lysines 9 and 14 (H3K9acK14ac), trimethylation of H3 lysine 4 (H3K4me3), trimethylation of H3 lysine 9 (H3K9me3), and trimethylation of H3 lysine 27 (H3K27me3). Our data indicate that a large number of human genes are regulated by a complex combinatorial usage of both active and repressive epigenetic marks. Moreover, using the epigenomic map, we have identified for the first time human Polycomb Response Elements (PREs), which are critical cis-elements to mediate the activities of PcG proteins. We show that these human PREs are associated with both PRC1 and PRC2 proteins in vivo. The transcriptional repression of reporter genes by the human PREs requires the presence of the epigenetic mark, H3K27me3, and PcG proteins. Furthermore, we demonstrate that human PREs function as bona fide PREs in Drosophila, implying that not only the trans PcG proteins but also certain features of the cis PREs are well conserved. Our data suggest that similar mechanisms are used in targeting the PcG proteins for transcriptional silencing in Drosophila and mammals.